Prokineticins are regulatory peptides that are thought to exert signaling activity via two highly conserved G protein-coupled receptors (GPCR), the prokineticin receptor 1 (PKR1) and the prokineticin receptor 2 (PKR2). Mature human prokineticins (PK1 and PK2) contain 86 and 81 amino acids, respectively, and are among the largest known ligands for all GPCRs. PK1 and PK2 share about 45% amino acid identity within and among several distinct species, and a sequence alignment readily suggests that numerous PKs exhibit complete conservation of the first six amino acids and the 10 cysteine residues predicted to form five pairs of disulfide bonds. Substitution or addition of any of the six amino acid residues in the N-terminus rendered the human PK1 inactive, and studies with chimeric proteins have shown the critical role of the cysteine-rich domain for bioactivity, although certain residue changes in the C-terminus were tolerable to at least some degree. Intriguingly, two of the N-terminus mutants with either substitution or addition of only a single amino acid resulted in mutant PKs that possessed antagonist activity, further indicating the importance of the N-terminal six residues in binding to and activating PKRs.
Over the last few years, a spectrum of biological functions ranging from development to adult physiology has been assigned to prokineticins. For example, prokineticins were reported as regulators of smooth muscle contractility in a study that used recombinant PK1 and PK2 to stimulate the contraction of guinea pig ileum. The role of PKs in gastric and colonic contractility has also been investigated, and histological studies revealed that PKR1 is also expressed on myenteric plexus neurons and colocalizes with a small subset of NOS synthetase-expressing neurons. Thus, PK may regulate gastrointestinal motility directly via activating smooth muscle cells, and indirectly via modulating the activities of enteric neurons. In another example, various studies have indicated the involvement of the PKs/PKRs in nociception. Among other data, intraplantar injection of recombinant PK2 caused a strong and localized hyperalgesia by reducing the nociceptive thresholds to thermal and mechanical stimuli, and systemic injection of frog PK2 homolog into rats induced hyperalgesia to tactile and thermal stimuli. Mice lacking the PKR1 gene were recently reported to exhibit impaired pain perception to various stimuli, including noxious heat, mechanical, capsaicin, and protons.
In yet another example, PK2 was reported to have a regulatory function in sleep regulation, circadian rhythm and stress response. It was observed that PK2 mRNA in the suprachiasmatic nucleus (SCN) displays dramatic circadian rhythmicity under light/dark and constant dark conditions and so suggests the potential regulatory function of PK2 for the circadian clock. Subsequently, multiple lines of evidence have supported the role of PK2 as a prominent output molecule for the SCN circadian clock. Furthermore, the receptor for PK2 is expressed in virtually all known primary SCN targets, indicating that these SCN targets can respond to oscillatory PK2 signal from the SCN. WO2007/067511 describes various compounds that are useful in the treatment or prevention of neurological and psychiatric disorders in which prokineticin receptors are involved, and especially for modulation of circadian rhythm and treatment of sleep disorders.
More recently, the role of PK2 in the regulation of anxiety and depression-related behaviors has also been investigated. For example, intracerebroventricular (ICV) infusion of PK2 increased anxiety behavior as assessed by elevated plus maze and light/dark box. ICV delivery of PK2 also led to increased depression-like behaviors in the tests of forced swimming and learned helplessness. Conversely, mice lacking the PK2 gene (PK2−/− mice) displayed significantly reduced anxiety and depression-like behaviors. Furthermore, PK2−/− mice show impaired responses to exposure to new environments in terms of locomotor activity, arousal, body temperature and food intake. These studies strongly suggest that PK2 signaling also plays a critical role in stress response and anxiety, and depression-related behaviors.
In still further known functions, prokineticins have been reported as potent modulators for angiogenesis, hematopoiesis, and neurogenesis. For example, PK1 was identified as a molecule that was capable of inducing proliferation of primary bovine adrenal-cortex-derived capillary endothelial (ACE) cells, and delivery of PK1 in ovary elicited potent angiogenesis and cyst formation, while the angiogenic effect is absent when delivered to cornea or skeletal muscles. PK1 and PK2 also drastically promoted the differentiation of mouse and human bone marrow cells into the monocyte/macrophage lineage, and PK2 promoted the survival and differentiation of granulocytic lineages in cultures of the human or mouse hematopoietic stem cells. Detailed expression analyses indicate that both PKR1 and PKR2 are expressed in the hematopoietic stem cells. Still further, PK2 has also been reported as regulator of neurogenesis for adult mammalian brain, and PK2 appears to function as a chemoattractant for SVZ-derived neuronal progenitors.
Consequently, prokineticin-mediated signaling has been the focus for certain methods and compositions for modulation of angiogenesis (e.g., U.S. Pat. App. No. 2004/0235732), and compositions and methods to modulate angiogenesis. For example, U.S. Pat. No. 7,323,334 teaches use of prokineticin receptor antagonists in the modulation of receptor signaling.
Therefore, while numerous compositions and methods related to prokineticin-mediated signaling have been described, there is still a need to explore and provide further compositions and methods for heretofore unknown uses.